Autoimmune diseases occur when a mammal's immune system fails to recognize some of the mammal's own tissues as “self” and attacks them as “foreign”. Normally, self-tolerance is developed early by developmental events within the immune system that prevent the mammal's T cell and B cells from reacting with the mammal's own tissues. Major Histocompatibility Complex (Major Histocompatibility Complex) cell surface proteins help regulate these early immune responses by binding to and presenting processed peptides to T cells.
When this self-tolerance breaks down, autoimmune diseases develop. Now, the mammal's own tissues and proteins are recognized as “antigens” and are attacked by the mammal's immune system. For example, multiple sclerosis is believed to be an autoimmune disease that occurs when the immune system attacks the myelin sheath. This sheath is thought to insulate and protect the nerves. The disease is a progressive one, characterized by demyelination, followed by neuronal loss and motor function loss. An additional example is rheumatoid arthritis (“RA”). RA is believed to be an autoimmune disease arthritis (“RA”). RA is believed to be an autoimmune disease which involves chronic inflammation of the synovial joints and infiltration by activated T cells, macrophages and plasma cells. This inflamation is thought to lead to a progressive destruction of the articular cartilage. It is the most severe form of joint disease. The nature of the autoantigen(s) attacked in rheumatoid arthritis is poorly understood, but collagen type II is a candidate.
Like autoimmune diseases, rejection of transplanted tissue also involves a hyper-response by the immune system to an antigen. This is manifested as graft rejection in the case of organ transplantation (host-versus-graft disease, or HVGD). Another manifestation of pathological immune reactivity is graft-versus-host disease (GVHD) that occurs in approximately 30% of bone marrow recipients. Up to half of those patients who develop GVHD may succumb to this process. This high morbidity and mortality has led to continuous interest in the possibility of controlling or preventing GVHD.
There are two forms of GVHD, acute and chronic. Acute GVHD develops within the first 3 months after bone marrow transplantation and features disorders of skin, liver and gastrointestinal tract. Chronic GVHD is a multiorgan autoimmune-like disease, emerging from 3 months up to 3 years post-transplantation and shares features common to naturally occurring autoimmune disorders, like systemic lupus erythematosus (SLE) and scleroderma.
Studies on the effect of Copolymer 1 on various processes involved in the pathological course of immune rejection showed that Copolymer 1 inhibited T cell proliferation in response to host cell (Aharoni et al., Immunology Letters 58(2):79–87, 1997). Copolymer 1 treatment completely abolished cytotoxic activity toward grafts, prevented the pro-GVHD IL-2 and IFN-γ cytokine secretion, and induced beneficial Th2 anti-inflammatory response. In view of these cumulative data, Copolymer 1 is a candidate drug for the prevention of HVGD and GVHD in humans. See WO 96/32119 and U.S. Pat. No. 5,858,964. Copolymer 1 has been suggested as a potential therapeutic agent for multiple sclerosis (Eur. J. Immunol. [1971] 1:242; and J. Neurol. Sci. [1977] 31:433; K. P. Johnson, 1 Neurology 65–70 (1995); N. Engl. J. Med. [1987] 317:408) and other immune system conditions, such as immune diseases and delayed-type hyper-sensitivity conditions (WO 00/05250). This drug is a synthetic polypeptide functionally crossreactive with myelin basic protein (MBP). MBP is a natural component of the myelin sheath.
Copolymer 1 has been shown to suppress experimental allergic encephalomyelitis (EAE) induced by various encephalitogens, including mouse spinal cord homogenate (MSCH). MSCH encompasses all myelin antigens, such as MBP (Sela M. et aL., 88 Bull. Inst. Pasteur 303–314 (1990), proteolipid protein (PLP) (Teitelbaum, D. et al., J. Neuroimmunol. (1996) 64:209–217) and myelin oligodendrocyte glycoprotein (MOG) (Ben-Nun A et al., 243 J. Neurol. (Suppl 1) S14–S22 (1996)) in a variety of species. EAE is an accepted model for multiple sclerosis.
It has also been demonstrated that Copolymer 1 is active when injected subcutaneously, intra-peritoneally, intravenously or intramuscularly (D. Teitelbaum et al., Eur. J. Immunol. (1971) 1:242–248; D. Teitelbaum et al., Eur. J. Immunol. (1973) 3:273–279). For instance, in phase III clinical trials, daily subcutaneous injections of Copolymer 1 were found to slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (K. P. Johnson, 1 Neurology 65–70 (1995); N. Engl. J. Med. [1987] 317:408).
Currently, all approved treatments of multiple sclerosis involve subcutaneous injection of the active substance. Frequently observed injection-site reactions include irritation, hypersensitivity, inflammation and pain and even necrosis (in the case of at least one interferon β 1-b treatment) and a low level of patient compliance. Therefore, an alternative method of administration is desirable. Thus, in order to effectively treat chronic diseases such as autoimmune diseases, oral, nasal or pulmonary formulations and methods for producing such formulations are necessary.
One way to overcome the difficulties in subcutaneous injection of drugs is to create a form that can be taken orally. EP Patent 359,783 discloses the treatment of autoimmune disease by oral administration of autoantigens. In addition, it describes the oral administration of MBP for the treatment of multiple sclerosis. Oral administration of an autoantigen has been termed “oral tolerance”.
PCT International Application Nos. WO 91/12816, WO 91/08760, and WO 92/06704 all depict the treatment of autoimmune diseases other than multiple sclerosis using the “oral tolerance” method with a variety of autoantigens. However, none of these references disclose the treatment of multiple sclerosis or other autoimmune diseases by the oral administration of a non-autoantigen such as Copolymer 1.
The invention also encompasses another avenue of administration that avoids the problems inherent in subcutaneous injection. This avenue is to produce a form of the drug that can be administered nasally.